Synthetic and environmental antigens are presented to T cells in the context Of MHC determinants but, for certain antigens, some determinants are more effective than others 1-3, perhaps because they make an optimal or more immunogenic physical association with the antigen z3. Here, Randy Mandell and Paul Sondel use the concepts of immune crossreactivity and'alien'MHC antigens to propose an alternative explanation for allele-specific MHC-restriction of T-cell responses to certain antigens. Such allele-specific, alien-driven diversity may also be relevant to the relationship between MHC determinants and immune response genes.

We previously proposed that genetic events which create MHC polymorphism in germ-line genes also act in some somatic cells to create a diverse population of cells expressing altered or'alien'MHC determinants 4. We predicted that some of these alien determinants would immunologically resemble alloantigens. Moreover, certain autologous MHC determinants associated with particular environmental antigens on cell surfaces cross-react with allogeneic MHC determinants 5'6. Therefore, alien MHC determinants may also cross-react with autologous MHC determinants in association with certain environmental antigens. We postulated that the frequent expression of various somatically generated alien MHC determinants throughout development could continuously prime T cells recognizing these alien'alloantigens'4. Part of this priming to alien MHC determinants could occur early in development, prior to contact with exogenous antigen. This would expand in advance the pool ofT cells reactive to alloantigens and to environmental antigens presented wkh autologous MHC molecules, which are crossreactive with the various alien MHC determinants. The theory presented in this article extends our hypothesis by proposing genetic mechanisms that would allow for the selectable expression of certain alien MHC determinants. These might optimize the expansion of T cells later capable of mounting protective responses to pathogens.